CAS/Crk coupling serves as a "molecular switch" for induction of cell migration.
Carcinoma cells selected for their ability to migrate in vitro showed enhanced invasive properties in vivo. Associated with this induction of migration was the anchorage-dependent phosphorylation of p130CAS (Crk-associated substrate), leading to its coupling to the adaptor protein c-CrkII (Crk). In fact, expression of CAS or its adaptor protein partner Crk was sufficient to promote cell migration, and this depended on CAS tyrosine phosphorylation facilitating an SH2-mediated complex with Crk. Cytokine-stimulated cell migration was blocked by CAS lacking the Crk binding site or Crk containing a mutant SH2 domain. This migration response was characterized by CAS/Crk localization to membrane ruffles and blocked by the dominant-negative GTPase, Rac, but not Ras. Thus, CAS/Crk assembly serves as a "molecular switch" for the induction of cell migration and appears to contribute to the invasive property of tumors.
Klemke
R L
RL
Department of Immunology, The Scripps Research Institute, La Jolla, California 92037, USA. klemke@scripps.edu
Leng
J
J
Molander
R
R
Brooks
P C
PC
Vuori
K
K
Cheresh
D A
DA
D000818:Animals; D019556:COS Cells; D002462:Cell Membrane / Q000737:chemistry / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology*; D050719:Crk-Associated Substrate Protein; D005109:Extracellular Matrix / Q000502:physiology; D019204:GTP-Binding Proteins / Q000737:chemistry / Q000378:metabolism; D015870:Gene Expression / Q000235:genetics / Q000502:physiology; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007328:Insulin / Q000494:pharmacology; D008565:Membrane Proteins / Q000032:analysis; D009362:Neoplasm Metastasis; D010179:Pancreas / Q000166:cytology / Q000473:pathology / Q000503:physiopathology; D010190:Pancreatic Neoplasms / Q000473:pathology; D010750:Phosphoproteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D011506:Proteins; D011518:Proto-Oncogene Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D050737:Proto-Oncogene Proteins c-crk; D011817:Rabbits; D050717:Retinoblastoma-Like Protein p130; D014407:Tumor Cells, Cultured; D014443:Tyrosine / Q000378:metabolism; D020744:rac GTP-Binding Proteins; D018631:ras Proteins / Q000737:chemistry / Q000378:metabolism; D018909:src Homology Domains
C493841:BCAR1 protein, human; D050719:Crk-Associated Substrate Protein; D007004:Hypoglycemic Agents; D007328:Insulin; D008565:Membrane Proteins; D010750:Phosphoproteins; D011506:Proteins; D011518:Proto-Oncogene Proteins; D050737:Proto-Oncogene Proteins c-crk; D050717:Retinoblastoma-Like Protein p130; D014443:Tyrosine; D019204:GTP-Binding Proteins; D020744:rac GTP-Binding Proteins; D018631:ras Proteins